A definitive diagnosis of the neurodegenerating Alzheimer's disease has been a goal since the disease was first described in 1906. Alzheimer's disease affects 10% of people older than 65 and is characterized by a progressive loss of cognitive function with an abnormal accumulation of β-amyloid senile plaques and neurofibrillary tangles in the brain as its hallmarks. Alzheimer's disease appears to be caused by the misassembly of the β-amyloid peptide, which is a 39-43 amino acid fragment derived from the amyloid precursor protein. This accumulation of these large extracellular aggregates of amyloid β-peptide onto a β-sheet structure forms the senile plaques characteristic of Alzheimer's patients. Histochemical detection of the senile plaques can be carried out using a variety of compounds that can bind to β-sheets. Similarly, neurofibrillary tangles are intracellular structures that are primarily composed of a misfolded protein called tau, which can also be detected by histochemical stains. Unfortunately, these histochemical stains are not suitable for use in living patients since these stains lack significant ability to cross the blood-brain barrier. Moreover, even if such agents could cross the blood-brain barrier, non-radiological detection would be very difficult. Therefore, it is desirable to develop radiotracers to detect the plaque and tangle binding sites, and the most desirable manner of detection is positron emission tomography (PET).
PET is a non-invasive test that helps physicians diagnose abnormalities, determine the extent of disease, prescribe treatment, and/or track progress in therapeutic intervention. Among other advantages, PET allows imaging of biochemical processes of the body well in advance of anatomical changes associated with abnormal physiological states (i.e., cancer, Alzheimer's, etc). In its most common form, PET scans provide images of tissue activity by measuring decay of positrons from a positron-emitting radiopharmaceutical to thereby locates and quantify “hot spots” for tissue activity related to the specific radiotracer.
Imaging agents using PET can therefore greatly enhance chances of early diagnosis of Alzheimer's disease, which then allows patients to obtain the best therapy and most efficient therapeutic drugs early in the disease progression. Development of imaging agents that detect the senile plaques associated with Alzheimer's disease is currently underway. For example, one class of PET imaging agents comprises selected aminonaphthalene backbones, which have been shown to target the polymeric form of the β-amyloid peptide associated with senile plaques and bind to neurofibrillary tangles. One radiofluorinated molecular imaging probe, 2-(1-{6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphtyl}ethylidene)malonitrile, also known as [18F]FDDNP, became the first diagnostic tool to relatively specifically image plaques and tangles (see e.g., U.S. Pat. Nos. 6,274,119 and 6,660,530). Further related compounds are described in U.S. Pat. App. No. 2007/0053831. However, [18F]FDDNP is highly lipophilic and consequently exhibits some nonspecific binding. Therefore, the results obtained from PET scans using [18F]FDDNP are often relatively poor in image quality and make diagnosis difficult.
Still other known labeling compounds include numerous substituted and radiolabeled benzofuran compounds as described, for example, in U.S. Pat. No. 7,173,061, and numerous substituted quinolinehydrazones as described, for example, in U.S. Pat. No. 6,589,504. Various substituted phenyl imidazo[1,2-b]pyridazine and similar structures are described as imaging agents in WO 2007/033080, and selected substituted benzathiazole compounds are known for labeling and are described in WO 2007/035405. Still further known compounds with more or less specific binding to amyloid are referred to in U.S. Pat. App. No. 2005/0048000. However, and similarly to FDDNP, such known compounds are often problematic with respect to their transport across the blood-brain barrier, stability under physiological conditions, and selectivity towards neurofibrillary tangles and/or senile plaques.
Therefore, while various compositions and methods for imaging senile plaques and/or neurofibrillary tangles are known in the art, all or almost all of them suffer from one or more disadvantages. Thus, there is still a need to provide improved imaging agents for the detection of senile plaques and neurofibrillary tangles.